PROJECT ABSTRACT: High-amplitude, fast brain deformation due to skull acceleration is the underlying cause of traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE). This project aims to provide new measurements of brain deformation needed to build and assess computer models of brain biomechanics, in injury-relevant regimes. Computer models of brain-skull mechanics are needed to understand TBI and CTE, and to develop rational approaches for prevention and treatment. The ability of current models to accurately predict injury-causing deformations in the intact, living human brain remains largely unknown. Previously we measured, for the first time, 3D strain in the human brain in vivo due to mild (sub-injury) head acceleration using tagged magnetic resonance (MR) imaging and a novel image analysis method, HARP-FE. We estimated anisotropic mechanical properties of brain tissue and characterized the brain-skull interface using MR elastography. We established the ability to compare simulated brain deformations to 3D strain fields measured in the live human brain. In the proposed project we will measure deformation in the pig brain at both low and high skull accelerations to understand the relationship between strains in sub-injury and injury regimes. In the pig brain we will seek relationships between local brain deformation and the occurrence and location of injury in both white matter and grey matter. We will also obtain data from 3D motion in the human brain at low skull accelerations, in subjects of different ages and genders. We will develop new strain mapping methods to enhance accuracy near the brain surface. Comparison of computer-predicted brain deformations to measured 3D brain deformations in the human and pig will be used to rigorously evaluate and improve computer models. Aim 1: Determine the relationship between brain deformation, head acceleration, and injury in the pig. Aim 2: Assess the effects of anatomy and physiology on acceleration-induced human brain deformation. Aim 3: Quantify and improve the ability of computer models to predict 3D brain deformation and injury. In Aim 1 we test the hypotheses that brain deformations due to low skull accelerations (i) predict sites of injury and (ii) scale nonlinearly to deformation under high skull acceleration. In Aim 2 we ask how individual and group (age/gender) differences in mechanical properties, skull-brain connections, and head geometry affect acceleration-induced brain deformation. In Aim 3, we will evaluate and improve computer models of TBI developed by our own team, and by the modeling community at large, by comparing spatiotemporal data from simulations and experiments to quantify accuracy and uncertainty. This project has already provided the first full-field, 3D strain estimates in the human brain. The proposed renewal extends this advance with studies that relate brain deformation directly to injury and identify factors that affect deformation. Successful completion of these Aims will lead to improved models of brain biomechanics with which to understand and combat TBI/CTE.